Is the gut important in multiple joint osteoarthritis? A multimodal investigation in humans and pet dogs

项目摘要 这项工作的中心假设是增加的肠道通透性(IP)，无论是直接的，或通过 相关的并存，促进多关节骨关节炎(MJOA)的发展和恶化。 多发性关节骨关节炎(MJOA；指个人体内多个关节部位的骨关节炎)很常见 但没有得到充分的研究。MJOA是进行性的，随着OA全身负担的增加，相关的疼痛和 残疾增加，治疗不那么成功。尽管MJOA产生了重大的社会影响，但大多数 骨性关节炎的研究仍然集中在单个关节上。迫切需要了解以下因素： 促进MJOA的进展和恶化。为了解决我们的假设，我们的团队可以访问一个大型、 人类患者的纵向队列，独特的是，可以在宠物中获得自然产生的MJOA模型 狗。没有MJOA的啮齿动物模型，但自然发生的MJOA的狗也有类似的疾病 表现与人类相比进展更快，使宠物狗成为理想的模型 探讨MJOA的潜在发病机制和可能的治疗方法。我们已经证明了炎症性 调解人与办公自动化的总体负担有关；这些风险因素和其他风险因素至少部分源于 肠道微生物群通过增加肠道通透性(IP；“肠漏”)。我们有证据表明 脂多糖(LPS)和脂多糖结合蛋白(LBP)，反映IP增加和暴露于 微生物产品)，促进办公自动化。此外，人类的血清脂多糖(和狗的血清LBP)呈阳性 与受MJOA影响的关节数相关联。为了进一步阐明IP作为一种机制在 MJOA，拟议的工作将利用人类和狗的研究：JoCoOA，一个超过 4,000名45岁及以上的黑人和白人男女；约翰斯顿县健康研究(JoCoHS)，一个 积极招募队列(2019-，n~2000)，包括年轻人(35-70岁)和西班牙裔个人；以及大量 在宠物狗身上容易接触到自然发生的MJOA的队列。来自所有三个队列的数据将被用于 实现以下三个目标。在目标1中，我们将确定改变的IP、 全身性炎症，以及人类和宠物狗的放射性和症状性MJOA。AIM 2将允许 识别预测MJOA发展和恶化的生物标志物并确定纵向 JoCoOA参与者和狗之间的全身炎症和IP标记物的相关性。在《目标3》中， 我们将测试一种益生素对IP、微生物群和MJOA症状的影响，方法是随机选择70只狗 MJOA(来自AIM 1)接受低聚果糖补充剂或安慰剂3个月，然后 炎症和IP的生物标记物的重新表征。这两项研究都将证实这种联系 在IP和MJOA增加和强有力地定义预测发展和恶化的生物标记物之间 为了解增加的知识产权如何促进MJOA和 确定治疗目标，以及提供识别高危个体进行先发制人管理的手段。

Project Summary The central hypothesis of this work is that increased intestinal permeability (IP), either directly, or via related comorbidities, promotes the development and worsening of multi-joint osteoarthritis (MJOA). Multiple joint osteoarthritis (MJOA; referring to OA in more than one joint site within an individual) is common but understudied. MJOA is progressive, and as whole-body burden of OA increases, associated pain and disability increases, and treatments are less successful. Despite the significant societal impact of MJOA, most OA research remains focused on individual joints. There is an urgent need to understand the factors that promote progression and worsening of MJOA. To address our hypothesis, our group has access to a large, longitudinal cohort of human patients, and, uniquely, access to the naturally occurring MJOA model in pet dogs. There are no rodent models of MJOA, but dogs with naturally occurring MJOA have similar disease manifestations with more rapid progression compared with humans, making pet dogs an ideal model in which to explore underlying mechanisms of MJOA and potential therapies. We have shown that inflammatory mediators are related to overall burden of OA; these and other risk factors may at least partly derive from the gut microbiome via increased intestinal permeability (IP; “leaky gut”). We have evidence that lipopolysaccharide (LPS) and LPS-binding protein (LBP, reflecting increased IP and increased exposure to microbial products), promote OA. Additionally, serum LPS in humans (and serum LBP in dogs) is positively associated with the number of joints affected by MJOA. To further elucidate the role of IP as a mechanism in MJOA, the proposed work will leverage human and dog studies: The JoCoOA, a longitudinal cohort of over 4000 Black and White men and women aged 45 and older; The Johnston County Health Study (JoCoHS), an actively enrolling cohort (2019-, n~2000) including younger (35-70 years) and Hispanic individuals; and a large cohort of readily accessible naturally occurring MJOA in pet dogs. Data from all three cohorts will be used to address the following three aims. In Aim 1, we will determine cross-sectional associations between altered IP, systemic inflammation, and radiographic and symptomatic MJOA in humans and pet dogs. Aim 2 will allow identification of biomarkers predictive of development and worsening of MJOA and determine longitudinal associations with markers of systemic inflammation and IP among JoCoOA participants and dogs. In Aim 3, we will test the effects of a prebiotic on IP, the microbiome and MJOA symptoms by randomizing 70 dogs with MJOA (from Aim 1) to receive either a fructooligosaccharide supplement or placebo for 3 months followed by re-characterization of biomarkers of inflammation and IP. These studies will both verify the association between increased IP and MJOA and robustly define biomarkers predictive of development and worsening MJOA, laying the groundwork for mechanistic studies to understand how increased IP promotes MJOA and to identify therapeutic targets, as well as provide means to identify at-risk individuals for preemptive management.